The incidence and management of cutaneous adverse events of the epidermal growth factor receptor inhibitors

Introduction

Although chemotherapy has long been associated with high incidence of side effects, skin complications have often been neglected or ignored by oncologists as minor issues. The advancement of molecular biology and the introduction of targeted therapy into day-to-day clinical practice, through which we can precisely act on the molecules involved in the pathomechanism of tumor development, has been accompanied by an increased interest in skin complications. Knowledge of the mechanisms of action of both conventional and targeted therapies is essential to understand the etiopathogenesis of such skin toxicity. Proper therapeutic treatment is however associated with maintaining good quality of life for patients, despite any side effects. Knowledge of possible complications concerning skin and its appendages and of their treatment and prevention so as to maintain or merely modify antineoplastic therapy is thus an important element of cooperation between oncologists and dermatologists.
The development of skin lesions during or after cancer treatment may be indicative of the side effects of a particular cytostatic drug, molecular drug, radiotherapy, adjuvant therapy, or the cancer itself. It should also be noted that some cutaneous side effects that arise during treatment with molecular-targeted drugs, such as dry skin, papulopustular rash, paronychia, and changes in the hair structure, may appear similar, despite the use of different drugs.
Epidermal growth factor receptor (EGFR) belongs to the Erb family of tyrosine kinase receptors, responsible for signaling from the outside to the inside of the cell. EGFR plays an important role in many physiological processes, and its main stimulators are EGF and TGF-. The epidermal growth factor receptor family consists of 4 membrane receptors with tyrosine kinase activity: EGFR (ErbB1, Her1), ErbB2 (Her2), ErbB3 (Her3), and ErbB4 (Her4) [1–3]. Overexpression of these receptors is found in many cancers, including malignant head and neck neoplasms, non-small-cell lung cancer, colorectal, cervical, prostate, breast, ovarian, stomach, and pancreatic cancer [4]. An excessive expression, and also defective mechanisms of EGFR inhibition lead to the progression of cancer through the activation of the signaling pathways responsible for cell proliferation and differentiation, the suppression of apoptosis, increased survival and metastasis, and angiogenesis. It is also associated with more advanced disease at the time of diagnosis and is an unfavorable prognostic factor [1, 5]. In clinical practice, drugs that affect the activity of EGFR are increasingly used. Among them the following should be particularly noted:
a) EGFR-blocking monoclonal antibodies: cetuximab and panitumumab;
b) EGFR tyrosine kinase inhibitors:
– first generation: gefitinib and erlotinib,
– second generation: trastuzumab, dacomitinib, necitumumab,
– third generation: osimertinib, rociletinib, pertuzumab, olmutinib, poziotinib, varlitinib, sapitinib, vandetanib;
c) multitarget tyrosine kinases inhibitors: lapatinib, neratinib, afatinib, canertinib [6–10].
EGF receptors are located in the membranes of epithelial cells and of mesenchymal cells, such as fibroblasts and chondrocytes. In the skin, EGFR activation regulates epidermal growth by stimulating proliferation and differentiation, and by inhibiting keratinocyte apoptosis [11, 12]. Stimulation of the receptor is associated with the transmission of a signal corresponding to the transfer of keratinocyte from the G1 phase to the S phase of the cell cycle [13]. EGF also affects the development of sweat and sebaceous glands and inhibits the growth of hair; it is also involved in angiogenesis by enhancing the expression of fibroblast growth factor binding protein (FGF-BP), a protein that binds and activates FGF-1 and FGF-2 [14].
Inhibition of EGFR activity significantly impairs epidermal homeostasis. The blocking of the domain function through receptor tyrosine kinase activity leads to inhibition of DNA synthesis and the blocking of the transition from the G1 to the S cell cycle phase [1]. As a result, increase of terminal keratinization markers in the basal layer of the epidermis is observed; this is responsible for the premature differentiation and retention of keratinocyte growth (including p27KIP1, KRT1, STAT3) [1, 11]. Under physiological conditions, these markers are found only in the upper layers of the epidermis. There is also inhibition of the maturation process through the influence on intercellular connections and the promotion of adhesion, which prevents the normal migration of keratinocytes from the basal layer to the stratum corneum of the epidermis. This results in a pronounced thinning of the epidermis, including the stratum corneum, which leads to impairment of the protective function due to an increase in its permeability [15]. The release of cytokines and the activation of the cells involved in the inflammatory response are responsible for excessive skin sensitivity and paronychia, associated with injuries [11]. As a result of these processes, characteristic skin lesions are formed, such as papules and pustules; the damaged barrier additionally increases the risk of developing secondary bacterial infections and other complications.
The inhibition of EGFR also strengthens UV-induced keratinocyte apoptosis. Under physiological conditions, UV radiation damages the DNA of keratinocytes by affecting the formation of free radicals. An increased expression of EGFR and intensification of proliferative signals occur in response. Disorders of this process can cause induced lesions or exacerbation of skin lesions upon exposure to UV radiation. Within the hair follicles, this process results is an increase in the expression of genes that stimulate inflammatory processes, apoptosis, and the blocking of ducts, leading to bursting [15, 16].
The mechanism leading to skin toxicity during treatment with EGFR inhibitors is not well known, but it is undoubtedly the result of modifications of the signals associated with its activation, particularly the RAS/RAF/MEK/ERK pathway, which affects cell cycle regulation, including proliferation and the differentiation of epidermis cells [17]. The disturbance of signal transmission in this pathway is responsible for the common features of skin lesions.
Adverse drug reactions of a similar nature include EGFR-directed monoclonal antibodies, EGFR tyrosine kinase inhibitors, and inhibitors of BRAF and MEK used to treat melanoma [18]. Despite the unmistakable similarities, the observed lesions may, however, vary slightly in character and severity (Table 1). This is due to the fact that the molecules used in molecular therapies modify the signal associated with EGFR activation to different degrees [19]. These observations indicate the need to adapt prophylactic and therapeutic treatments not to the type of the drug, but rather to the group of drugs that modify the pathways associated with EGFR activation (Table 2). Similar treatment to prevent the development of undesirable effects and to control their progression if they occur can be successfully used for the whole group of signal modifying drugs EGFRRAS/RAF/MEK/ERK. The differences arising from the different summary of product characteristics will relate to the cases in which it is necessary to adjust the dose or interrupt the treatment, depending on the severity of the side effects (CTCAE, the Common Terminology Criteria for Adverse Events) [19, 20].

Xerosis

Xerosis is a problem in up to 33% of patients treated with EGFR inhibitors and is significantly dependent on the dose of the drug. Usually, it is most severe within the extremities and intensifies during therapy. In case of using EGFR tyrosine kinase inhibitors, skin dryness was found in 11% of those treated with gefitinib and 12% of those with erlotinib. Relatively dry skin was reported by 3% of patients treated with lapatinib [19]. It appears relatively late, about 30–60 days after the start of treatment; it is directly due to the inhibition of proliferation and differentiation of keratinocytes. Dry skin is also a cause of increased susceptibility to injuries and fissures, whose secondary causes include bacterial and viral infections. Deep painful fissures are most often seen in the area of fingertips, heels, periungual skin and dorsal surface of the interphalangeal joints [20]. The risk of skin dryness during treatment increases with age, pre-eczema, and prior cytotoxic use. Proper skin care significantly reduces xerosis.

Pruritus

Pruritus, an unpleasant sensation leading to scratching, occurs among 57% of patients treated with panitumumab, 10% of those with cetuximab, and 13% of those treated with erlotinib [19]. During treatment, generalized or localized itching was observed, ranging in strength from mild to severe pruritus. It often coexists with xerosis and papulopustular rash [11]. It is therefore worth stressing that proper skin care and the management of papulopustular rash can significantly alleviate symptoms. The mechanism that leads to pruritus during therapy with drugs that inhibit EGFR activity has not been explained. It is also unknown what effect its development has on its classical mediators, such as histamine and neurotransmitters, including serotonin, opioids, and -aminobutyric acid [21, 22].

Papulopustular rash

Papulopustular rash is one of the most common skin complications of EGFR activity modifying therapy [23]. It is reported in 45–100% of patients, depending on the literature data. It is most common during therapy with cetuximab and panitumumab, for monoclonal antibodies which the percentage of patients with lesions is 88–90% and 100%, respectively. Most cases are mild to moderate, with less than 5–18% of patients experiencing severe changes that significantly affect quality of life. When using EGFR tyrosine kinase inhibitors, rash is reported in 43–54% of gefitinib and 75% of erlotinib users. During treatment with lapatinib, papulopustular rash was reported in 13–47% of patients [19]. The discrepancies in the data for the individual drugs in the literature are mainly due to the classification of the different types of skin rashes into one group.
Skin lesions of pustular and papular types may be monoform or multiform, and mainly affect the face, scalp, and upper chest and back (the seborrheic areas). In severe cases, the lower parts of the body, buttocks, and limbs may also be affected. In the literature, they are usually described as acne-like (or acneiform), but unlike acne vulgaris, comedos or purulent cysts are not found [24]. The lesions develop in several stages, often after exposure to UV radiation. Although UV radiation may exacerbate changes, studies have not shown photoprotection to prevent their development, because the presence of the rash depends primarily on the type and dose of the drug used. Excessive sebum secretion is not associated with an increased risk of lesions, but attention should be drawn to the fact that prior predisposition to folliculitis and acne can be associated with skin adverse events during therapy with EGFR inhibitors. In more than 75% of patients, the first lesions appear in the first 1–2 weeks of treatment. Erythema and edema usually appear first, accompanied by sensory disturbances, and then between the second and fourth week, folliculitis and/or pustular lesions and pruritus occur. At about 4 weeks, the lesions stabilize and, if properly treated, disappear, leaving transient erythema and telangiectasia [11, 12, 24]. The duration and severity of symptoms depend on the dose of the drug, and the symptoms may also self-relieve, despite continued therapy. Complete disappearance of lesions is observed about one month after the end of treatment. Persistent hyperpigmentation was observed in patients with dark skin complexion. The lesions may be accompanied by paronychia.

Paronychia

Paronychia and nail lesions occur in 25% of patients treated with panitumumab and 16% of those treated with cetuximab [19]. For gefitinib and erlotinib therapy, they are reported in 3–10% and 14% of patients, respectively. Relatively infrequently (1%), paronychia is seen among patients treated with lapatinib.
Paronychia is an inflammation characterized by edema, redness, and soreness in the area around the nail plate. It can affect one or more fingers and toes. In most cases, it has a mild course but, in some cases, bleeding granulation and pockets develop, from which squeezing elicits pus. In such cases, there are usually secondary bacterial and fungal infections. Paronychia frequently accompanies papulopustular rash. It develops later on, usually 4–8 weeks after starting treatment [1, 19].

Hair changes (alopecia and changes in hair structure)

Alopecia is reported in 6% of patients treated with erlotinib and 5% of those treated with cetuximab [19]. Nonscarring hair loss is reversible, slow, and usually does not lead to complete baldness. These changes can be accompanied by alterations in the hair structure (curly hair, thin), along with a change in color [11, 19]. This applies mainly to the scalp, but may also affect other areas of the body. The lesions develop 2–5 months after the onset of treatment. Blocking the signal mediated by EGFR leads to the blockade on the hair growth cycle, that is, the hair transitions from the anagen to the telogen phase. Disturbance of the normal hair cycle is the cause of delayed hair growth and changes in structure [19, 25]; inflammation processes are additionally activated within the hair follicle. Alopecia and structural changes are not the only described changes to hair during treatment with EGFR inhibitors. Patients may also have excessive eyelash growth (trichomegalia) and excessive hypertrichosis, including of the face. In these cases, it is recommended to trim eyelashes and use depilatory treatments, including laser depilation and eflornithine creams [11, 21].

Severe skin reactions

Serious drug-induced skin reactions have been occasionally reported, including cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Lyell’s syndrome) [11, 19, 25]. Therapy (such as systemic glucocorticosteroids, cyclosporine A) should be applied depending on the severity of the skin lesions and the accompanying symptoms (mucous membrane and/or conjunctiva erosions or systemic involvement). In case of anaphylaxis (acute urticaria, Quincke’s edema), standard antishock treatment should be implemented. In case of a serious skin drug reaction, it is very important to exclude its induction by drugs taken for other reasons.

Recall reaction

Recall reactions are rare, unforeseeable skin reactions occurring in previously irradiated sites [26]. The occurrence of a memory reaction depends on personal characteristics as well as on the type of the cytotoxic drug used. The drugs that most commonly contribute to the occurrence of these skin disorders include gemcitabine, capecitabine, methotrexate, docetaxel, etoposide, and doxorubicin. Such reactions have also been observed following the application of new oncological treatment therapies, such as pemetrexed [27, 28] and gefitinib [29], and also in the combinations of trastuzumab with vinorelbine [30], and of bevacizumab with gemcitabine [31]. It is not certain whether the dose of the drug affects the onset of the recall reaction, as similar complications have been observed with different doses. Recall reactions are as common in monotherapy as in complex therapy. No relationship between radiation doses and the risk of these lesions has been demonstrated [32].
The exact pathomechanism has not yet been understood. Several hypotheses have been advanced, but none of them has been confirmed by reliable research [26, 33–36]. It is believed that the pathomechanism involves damage to DNA that has been exposed to ionizing energy after the subsequent use of chemotherapy.
The skin lesions observed in this reaction vary in severity. The most common lesions seen with recall reactions are mild to moderate urticaria and erythema with accompanying dryness and desquamation of the skin or pruritus. However, with the increase in the severity of skin toxicity in the course of this reaction, painful swelling, blisters, or papulopustular rash appear. In very severe cases, ulcerations may develop and even necrotic lesions may occur [26, 33, 34]. The characteristic histopathological changes observed in these complications are mixed non-specific inflammatory infiltrates [32, 35]. These lesions mostly occur in the mild and moderate form. In contrast, severe lesions occur only in 10% of cases.

Summary

The correct treatment of cutaneous side effects may significantly improve the effectiveness of antineoplastic therapy. Skin lesions negatively affect the quality of life of patients, and controlling their symptoms may reduce the need to modify the dose and to interrupt treatment. It should be noted that, despite the sometimes great intensity of lesions, most of them do not in themselves represent a threat to the life or health of patients. The direct relationship they have with the cancer treatment indicates that their occurrence should be expected in each patient. In addition, it may be the case that prophylactic and therapeutic treatment will not alter the outcome, but only improve it, due to the presence of a provoking agent, namely, taking the medicine. Informing the patient of the causes of this situation may, in difficult cases, incline the patient to continue treatment. This is particularly justified in that some studies have documented the association of cutaneous toxicity with better therapeutic outcomes. Treatment algorithms should help guide proper treatment which, as one gains experience, can be modified and smoothly adapted to particular patients. In some cases, however, cutaneous toxicity will become the crux of a clinical problem that requires the cooperation of professionals in many fields.

Conflict of interest

The authors declare no conflict of interest.

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